Identifying Systemic Sepsis

The body develops compensatory mechanisms to prevent systemic inflammation in response to stress and injury. As overwhelming inflammation is rapidly lethal, these mechanisms have a protective effect during the first few hours after injury. However, they become deleterious as nearly all immune functions are compromised.The term “immunoparalysis” describes the global incapacity of the body to mount any kind of immune response; the extent of immunoparalysis is thought to correlate with life-threatening secondary infections and mortality. The hypoimmune state might require proinflammatory therapies to enhance immune function, but establishing the presence of immunodepression is crucial when considering such an approach. This article discusses methods for diagnosing immunoparalysis, in particular measurements of circulating monocyte human leukocyte antigen type DR expression and plasma interleukin-10.

Despite great improvements in critical care medicine over the past 20 years and numerous trials of anti-inflammatory drugs, sepsis, severe sepsis, and septic shock remain the leading cause of death in intensive care units [1,2]. Hypotheses of the pathophysiology of septic shock have evolved to take into account the disappointing results of many clinical trials, and it is now thought that death from septic shock may be due to distinct mechanisms that change as the condition progresses. At onset, septic shock is characterized by the overwhelming release of inflammatory mediators, which are responsible for organ dysfunction and hypoperfusion [3]. As sepsis persists, a shift towards an antiinflammatory state is observed and patients develop features consistent with immunosuppression [4–9]. Importantly, it seems that the majority of shock-related deaths occur during this secondary hypoimmune state. Indeed, an ongoing study by Monneret et al. that has so far enrolled 120 patients with septic shock has observed that 70% of nonsurvivors are still alive 3 days after the onset of shock (personal communication, 2004). It has been proposed that patients who survive the initial hyperinflammatory response but subsequently die from sepsis are those who do not recover immune function. The mortality rate in these patients may be explained by their inability to clear the initial infection and a predisposition to nosocomial infection [4-9]. This may account for the failure of therapies aimed at blocking the inflammatory cascade [10]. The therapeutic window for initiating treatment with anti-inflammatory drugs is very narrow (likely to be <24 h), after which a treatment to increase immune function may be more beneficial (Fig. 1).

Two animal studies have demonstrated the complexity of treating sepsis. The first focused on tumor necrosis factor-a (TNF-a) therapy. Although this cytokine has been identified as one of the key inflammatory mediators of adverse effects during the first phase of septic shock, clinical studies of anti-TNF-a therapies have not demonstrated improved outcomes. However, therapy to increase TNF- a levels reversed sepsis-induced immunosuppression and improved survival in a murine model of cecal ligation and puncture (CLP) [11]. The second study found that blocking the anti-inflammatory cytokine interleukin-10 (IL-10) before the induction of sepsis in mice increased mortality, whereas blocking IL-10 12 h after CLP improved survival [12]. These studies illustrate the importance of timing, indicating that a different therapy may have effects at different times.